Nuclear factor-kappa B mediates the cell survival-promoting action of activity-dependent neurotrophic factor peptide-9

Activity-dependent neurotrophic factor (ADNF) is produced by astrocytes in response to neuronal depolarization and, in turn, promotes neuronal surviva l. A nine-amino acid ADNF peptide (ADNF9) exhibits full neurotrophic activi ty and potently protects cultured embryonic rat hippocampal neurons from ox idative injury and apoptosis. Picomolar concentrations of ADNF9 induced an increase in nuclear factor-kappa B (NF-kappa B) DNA-binding activity within 1 h of exposure, with a maximum increase of similar to 10-fold by 6 h. Act ivation of NF-kappa B was correlated with increased resistance of neurons t o apoptosis induced by exposure to Fe2+. The antiapoptotic action of ADNF9 was abolished when NF-kappa B activation was specifically blocked with kapp a B decoy DNA. Oxidative stress was attenuated in neurons pretreated with A DNF9, and this effect of ADNF9 was blocked by kappa B decoy DNA, suggesting that ADNF9 suppresses apoptosis by reducing oxidative stress. ADNF9 also p revented neuronal apoptosis following trophic factor withdrawal via an NF-k appa B-mediated mechanism. Thus, NF-kappa B mediates the neuron survival/pr omoting effects of ADNF9 in experimental models relevant to developmental n euronal death and neurodegenerative disorders.